Oxidized thioredoxin-1 restrains the NLRP1 inflammasome [NTERT-1]
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ABSTRACT:
PROVIDER: PRJNA888113 | ENA |
REPOSITORIES: ENA
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Project description:Oxidized thioredoxin-1 restrains the NLRP1 inflammasome.
| PRJNA888111 | ENA
Project description:Oxidized thioredoxin-1 restrains the NLRP1 inflammasome [mBMDM]
| PRJNA888114 | ENA
Project description:The danger signals that activate the NLRP1 inflammasome have yet to be firmly established. NLRP1 undergoes autoproteolysis to generate N-terminal (NT) and C-terminal (CT) fragment, which importantly, is a necessary step for its check-point regulation by the DPP9 ternary complex and the mechanistic activation of NLRP1 through functional degradation. Here, we report an added layer of regulatory complexity to NLRP1 activity, in the form of a repressive interaction that NLRP1 forms with the oxidized, but not reduced, form of thioredoxin-1 (TRX1). Loss of TRX1 destabilizes the NT fragment of NLRP1 and promotes enhanced inflammasome activation. The TRX1 interaction occurs through the NACHT-LRR of NLRP1 and requires nucleotide binding in its ATPase domain. In addition, we found that several patient-derived and ATPase-inactivating mutations in the NACHT-LRR region hyperactive the inflammasome by destabilize protein folding and are also shown to abrogate TRX1 binding. Thus, NLRP1 appears to detect intracellular reductive stress through a decrease in the fraction of intracellular oxidized TRX1, which enhances protein disorder, leading to inflammasome signaling. These findings link the cellular redox environment to NLRP1-mediated innate immunity.
2022-11-04 | GSE215035 | GEO
Project description:The danger signals that activate the NLRP1 inflammasome have yet to be firmly established. NLRP1 undergoes autoproteolysis to generate N-terminal (NT) and C-terminal (CT) fragment, which importantly, is a necessary step for its check-point regulation by the DPP9 ternary complex and the mechanistic activation of NLRP1 through functional degradation. Here, we report an added layer of regulatory complexity to NLRP1 activity, in the form of a repressive interaction that NLRP1 forms with the oxidized, but not reduced, form of thioredoxin-1 (TRX1). Loss of TRX1 destabilizes the NT fragment of NLRP1 and promotes enhanced inflammasome activation. The TRX1 interaction occurs through the NACHT-LRR of NLRP1 and requires nucleotide binding in its ATPase domain. In addition, we found that several patient-derived and ATPase-inactivating mutations in the NACHT-LRR region hyperactive the inflammasome by destabilize protein folding and are also shown to abrogate TRX1 binding. Thus, NLRP1 appears to detect intracellular reductive stress through a decrease in the fraction of intracellular oxidized TRX1, which enhances protein disorder, leading to inflammasome signaling. These findings link the cellular redox environment to NLRP1-mediated innate immunity.
2022-11-04 | GSE215034 | GEO
Project description:To find cellular protein binding partners of the NLRP1 inflammasome, FLAG-tagged full length NLRP1 (or a GFP-FLAG protein control) was ectopically expressed in HEK 293T cells and affinity purified from cell lysates (Note: the NLRP1-FLAG-containing lysate samples were affinity purified in the presence or absence of excess proline) before proteins were reduced, alkylated, and trypsinized before TMT labelling and pooling of the differentially tested lysates to give three conditions (1. NLRP1-FLAG; 2. GFP-FLAG; 3. NLRP1-FLAG+proline) in duplicate. These data represent the results following sample and data processing.
2022-11-04 | PXD037391 | Pride
Project description:The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.
| S-EPMC9850498 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-04 | GSE215036 | GEO
Project description:We profiled the transcriptional changes in N/TERT-1 immortalized keratinocytes after doxycylin induction of gain-of-function mutants of the inflammasome sensor protein NLRP1.
2016-09-15 | GSE85791 | GEO
Project description:Inflammasomes are multiprotein complexes formed in response to pathogens. NLRP1 and CARD8 are related proteins that form inflammasomes, but the pathogen-associated signal(s) and the molecular mechanisms controlling their activation have not been established. Inhibitors of the serine dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) were recently discovered to activate both NLRP1 and CARD8. Interestingly, DPP9 binds directly to NLRP1 and CARD8, and this interaction, in addition to DPP9’s catalytic activity, may contribute to the inhibition of NLRP1. Here, we use activity-based probes, reconstituted inflammasome assays, and mass spectrometry-based proteomics to further investigate the DPP9-CARD8 interaction. We show that the DPP9-CARD8 interaction, unlike the DPP9-NLRP1 interaction, is not disrupted by DPP9 inhibitors or mutations that block autoproteolysis. Moreover, wild-type, but not catalytically-inactive mutant, DPP9 rescues CARD8-mediated cell death in DPP9 knockout cells. Together, this work reveals DPP9 activity and not direct protein binding restrains the CARD8 inflammasome, and suggests the binding interaction likely serves some other biological purpose.
2019-10-23 | PXD015047 | Pride
Project description:Neutralization of Oxidized Phospholipids Restrains Nonalcoholic Steatohepatitis
| PRJNA575823 | ENA